USP33, a new player in lung cancer, mediates Slit-Robo signaling

Wen, Pushuai; Kong, Ruirui; Liu, Jianghong; Zhu, Liangru; Chen, Xiaoping; Li, Xiaofei; Nie, Yongzhan; Wu, Kaichun; Wu, Jane Y.

doi:10.1007/s13238-014-0070-z

Cited by 39 publications

(42 citation statements)

References 38 publications

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“…For example, ubiquitin-specific protease 33 (USP33) was shown to be down-regulated in breast cancer (YuasaKawada et al 2009), lung cancer (Wen et al 2014) and colorectal cancer (Liu et al 2016b). On the other hand, we previously reported the enhanced expression of ubiquitinspecific protease 7 (USP7) in ovarian cancer (Ma and Yu 2016), which revealed that different ubiquitin-regulated enzymes may show completely different functions in tumor regulation.…”

Section: Introductionmentioning

confidence: 99%

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

2017

Tohoku J. Exp. Med.

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Transducin (β)-like 1 X-linked receptor 1 (TBL1XR1) is a core component of the NCoR/SMRT transcription co-repressor complex, and its role in regulating cancer progression has been reported. Serous epithelial ovarian cancer (EOC) is the most common histological type of EOC. Here we explored the significance of TBL1XR1 expression in predicting outcomes of patients with serous EOC. Real-time quantitative PCR analysis showed that the expression level of TBL1XR1 mRNA was significantly higher in EOC tissues compared with adjacent non-tumorous tissues. The protein levels of TBL1XR1 in EOC tissues were assessed by immunohistochemistry, and the patients were classified into low-expression group (n = 62) and high-expression group (n = 54) according to the immunoreactivity. Prognostic significance of TBL1XR1 was evaluated by univariate and multivariate analyses, showing that over-expression of TBL1XR1 was correlated with poor prognosis. In addition, TBL1XR1 was positively associated with the lymph node metastasis of EOC. Because vascular endothelial growth factor (VEGF)-C is known as a critical mediator of lymph node metastasis, we measured the expression level of VEGF-C mRNA in EOC tissues and thus identified a positive correlation between TBL1XR1 and VEGF-C mRNA levels. Subsequently, using human EOC cell lines, we showed that silencing of TBL1XR1 decreased VEGF-C expression, suggesting that TBL1XR1 may function as an upstream regulator of VEGF-C in EOC. Furthermore, the proliferation and invasion of EOC cells were inhibited by TBL1XR1 silencing. In conclusion, TBL1XR1 overexpression may be an unfavorable prognostic factor for EOC. We also suggest that the TBL1XR1-VEGF-C axis may determine the EOC progression.

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Section: Introductionmentioning

confidence: 99%

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

2017

Tohoku J. Exp. Med.

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“…The functional significance of USP33 has been investigated in breast, colon and lung cancer cells. USP33 can inhibit the migration of these cells by its deubiquitinating activity on Robo [38][39][40]. Here, we found that USP33 could deubiquitinate and stabilize PPM1A (Fig.…”

Section: Cellular Physiology and Biochemistry Cellular Physiology Andmentioning

confidence: 54%

Radiation Enhances the Epithelial– Mesenchymal Transition of A549 Cells via miR3591-5p/USP33/PPM1A

Zhong

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Radiotherapy plays a critical role in lung cancer treatment. Radiation can activate transforming growth factor-β (TGF-β) signaling and induce the epithelial-mesenchymal transition (EMT), which may lead to distant metastases. MicroRNAs (miRNAs) have been suggested to affect radiotherapy in lung cancer. Methods: miRNA Next-Generation Sequencing was performed to investigate the effects of irradiation on the miRNA profile of lung cancer A549 cells. The functions of identified miRNA on the radiation induced EMT and TGF-β activation in A549 cells were then explored. Protein expression was evaluated by western blotting. Immunofluorescence staining was performed to detect the localization of Snail. Luciferase Assay was used to determine the target gene regulated by the identified miRNA. Results: Radiation time-dependently induced EMT in A549 lung cancer cells as indicated by the changes of morphology, the expression of EMT marker proteins (E-cadherin, α-SMA and Vimentin) and the nuclear localization of Snail. Moreover, miR-3591-5p was identified as the most significant increased miRNA in response to radiation, and further experiments indicated that miR-3591-5p was required for radiation induced EMT and TGF-β/ Smad2/3 activation. Ubiquitin Specific Peptidase 33 (USP33) was a downstream target of miR-3591-5p as predicted by TargetScan and validated by 3’ untranslated regions (UTRs) Luciferase Assay. USP33 could deubiquitinate PPM1A (protein phosphatase, Mg2+/Mn2 + dependent 1A), a phosphatase for Smad2/3. Ectopic expression of USP33 or PPM1A partially abolished the effects of miR-3591-5p on EMT and TGF-β/ Smad2/3 activation. Conclusion: The present study revealed the critical role of miR-3591-5p/USP33/PPM1A in radiation-induced EMT via TGF-β signaling and may suggest novel radiation sensitise strategies for lung cancer.

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“…Recent studies have reported that USP33 may mediate oncogenic signaling through the Slit-Robo signaling pathway in colorectal cancer and breast cancer [18-20]. To further explore the potential mechanism that might be involved in the USP33-associated malignant progression of PTC, we firstly tested the protein expression patterns of Robo1 in PTC tissues, and identified the positive correlations between Robo1 and USP33 levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Taking into consideration that USP33 is an enzyme catalyzing deubiquitinate process, the interaction with Robo1 may modulate its ubiquitinating status. Indeed, several studies have reported that the ubiquitination of Robo1 was negatively regulated by USP33 [20, 27]. However, we cannot ignore other potential effects by USP33-Robo1 interaction.…”

Section: Discussionmentioning

confidence: 96%

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USP33 is a Biomarker of Disease Recurrence in Papillary Thyroid Carcinoma

Meng

Guo

2018

Cell Physiol Biochem

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Background/Aims: To investigate the clinical significance and functional mechanisms of deubiquitinase USP33 in papillary thyroid carcinoma (PTC). Methods: Immunohistochemistry staining was conducted to explore the expression of USP33 in PTC tissues and adjacent normal thyroid tissues. Patients’ prognosis was evaluated by disease-free survival. The prognostic role of USP33 was tested by univariate and multivariate analyses. To confirm the effect of USP33 in cell proliferation and invasion, overexpression and knockdown of USP33 were performed in two PTC cell lines. Besides, cell cycle, immunoprecipitation, and apoptosis experiments were conducted to further explore the signaling pathways. Results: By analyzing series of 158 PTC tissues, we found that USP33 was down-regulated in tumor tissue compared with normal thyroid tissues, which was closely associated with lymph node metastasis (P<0.001). In particular, univariate and multivariate analyses indicated that USP33 was an independent prognostic biomarker for PTC, low USP33 expression indicated high recurrence risk. Cellular studies with TPC-1 and BCPAP cells demonstrated that USP33 can attenuate the cell capacities of proliferation, migration and invasion. Fluorescence-activated cell sorting experiment found no significant effect of USP33 on cell cycle, whereas the apoptotic caspase proteins were activated by USP33-overexpression. Moreover, the interaction between USP33 and Robo1 protein was identified, and knockdown of Robo1 enhancing the oncogenic effect upon USP33-knockdown, suggesting that USP33 may inhibit tumor progression through Robo1 signaling. Conclusions: Our data demonstrated that USP33 downregulation in PTC tissues was correlated with poor clinical outcome, which may serve as a novel biomarker and potential therapeutic target.

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USP33, a new player in lung cancer, mediates Slit-Robo signaling

Cited by 39 publications

References 38 publications

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

Radiation Enhances the Epithelial– Mesenchymal Transition of A549 Cells via miR3591-5p/USP33/PPM1A

USP33 is a Biomarker of Disease Recurrence in Papillary Thyroid Carcinoma

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